Prostate cancer is the most common male malignancy and the second leading cause of cancer death in American men. The current standard therapies include surgery, radiation or adjuvant hormonal therapy. Although these therapies are relatively effective in the short-term, majority of patients initially diagnosed with localized prostate cancer ultimately relapse. Therefore, the major risk faced by prostate cancer patients is the development to metastasis. Intensive efforts are underway to develop therapeutics for the treatment of prostate cancer. Among all approaches, gene modulation is one of the most promising strategies due to the fact that genomic instability is the hallmark of cancer development. IKK1 is recently identified as the critical activator of prostatic epithelia cells to the metastatic fate. This application is the first attempt to evaluate the in vivo therapeutic efficacy of IKK1 by silencing its gene expression using small interfering RNA (siRNA). We have identified one potent IKK1 siRNA and demonstrated its ability to inhibit the migration of two prostate cancer cells. We will design a targeted delivery strategy to deliver the siRNA to prostate cancer cells. The objective is to develop an aptamer conjugated siRNA (aptamer-siRNA) targeting IKK1 gene to treat prostate cancer. Backbone modification and ligand conjugation will be conducted to overcome two obstacles of siRNA's therapeutic application: the in vivo stability and target-ability. The results of this study can lead to efficient siRNA therapeutics against prostate cancer. Our overall hypothesis is that the prostate cancer cells'growth and metastasis can be inhibited by the targeted delivery of IKK1 siRNA to tumor cells via conjugation with an aptamer which can recognize and bind to the PSMA (prostate specific membrane antigen) on the surface of prostate cancer cells (Fig. 1). We will test following specific hypotheses: i) silencing IKK1 can inhibit the invasive properties of prostate cancer cells;ii) silencing IKK1 could restore the gene expression of Maspin;iii) 2'-OMe modification in the sense strand of IKK1 siRNA will increase the in vivo stability without interfering its silencing effect;iv) conjugation of the anti-PSMA aptamer to siRNA will increase its uptake by prostate cancer cells;v) the increased uptake of siRNA in the tumor cells will correlate with higher anti-metastasis effect in the mouse prostate cancer model. PUBLIC HEALTH RELEVANCE: Prostate cancer is the most common male malignancy and the second leading cause of cancer death in American men. Successful accomplishment of this project will provide an effective therapeutics to treat prostate cancer.